Abstract：
:Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL) rabbits and to inhibit Cu2(+)-induced lipid peroxidation of isolated plasma low-density lipoproteins (LDL). After 84 days of feeding 1% of each compound in rabbit chow, probucol was effective in lowering serum cholesterol, whereas 2-4 were not. The concentration of drug in serum and LDL was 2 greater than 1 greater than 3 greater than 4. Probucol and analogues prevented Cu2(+)-induced oxidation of LDL in vitro to an extent that directly related to their concentrations in LDL. The decrease in lipid oxidation was directly correlated with the inhibition of both oxidized-LDL-induced cholesteryl ester synthesis in cultured macrophages and to the inhibition of aortic atherosclerosis in vivo. These results show that the antioxidant activity of probucol and analogues is directly related to their concentration in LDL, which may explain their pharmacological activity in reducing atherosclerosis.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Mao SJ,Yates MT,Rechtin AE,Jackson RL,Van Sickle WAdoi
10.1021/jm00105a046subject
Has Abstractpub_date
1991-01-01 00:00:00pages
298-302issue
1eissn
0022-2623issn
1520-4804journal_volume
34pub_type
杂志文章abstract：:We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0200815
更新日期：2002-07-04 00:00:00
abstract：:Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00049a008
更新日期：1994-11-11 00:00:00
abstract：:Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizure...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00019a019
更新日期：1995-09-15 00:00:00
abstract：:A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB(1) cannabinoid receptor has been evaluated. These compounds are derived from the previously described cannabinoid ligands 5,5'-diphenylimidazolidine-2,4-dione (hydantoins)....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049263k
更新日期：2005-04-07 00:00:00
abstract：:Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity consi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a007
更新日期：1980-01-01 00:00:00
abstract：:The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501998m
更新日期：2015-05-14 00:00:00
abstract：:In order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites, iodinated derivatives of tomoxetine were synthesized and evaluated in radioligand binding assays. Iodotomoxetine derivatives showed high affinity for serotonin (5-HT) uptake sites using a rat cortical membrane prepar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00101a029
更新日期：1992-11-13 00:00:00
abstract：:To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0304562
更新日期：2004-01-15 00:00:00
abstract：:We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revea...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101031u
更新日期：2011-01-13 00:00:00
abstract：:Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resist...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00347
更新日期：2020-07-23 00:00:00
abstract：:In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must be extremely potent and long acting and exhibit negligible side effects such as stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-D...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00101a003
更新日期：1992-11-13 00:00:00
abstract：:The diester 2a obtained from 1,1'-ferrocenedicarboxylic acid and the highly and indiscriminately cytotoxic fungal metabolite illudin M (1) displayed antiproliferative activity at submicromolar IC(50) (72 h) values against a panel of eight cancer cell lines. Compound 2a was about 40 times less toxic than 1 to nonmalign...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200359n
更新日期：2011-09-22 00:00:00
abstract：:We present a novel method to better investigate adverse drug reactions in chemical space. By integrating data sources about adverse drug reactions of drugs with an established cheminformatics modeling method, we generate a data set that is then visualized with a systems biology tool. Thereby new insights into undesire...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801546k
更新日期：2009-05-14 00:00:00
abstract：:Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the centr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800321h
更新日期：2008-09-11 00:00:00
abstract：:A quantitative structure-activity relationship (QSAR) study was performed on a set of 49 negative allosteric modulators of AMPA receptor, acting as anticonvulsant agents, using multiple linear regression. The predictive ability of the resulting model was evaluated against a set of 12 compounds; the results showed good...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0310838
更新日期：2004-03-25 00:00:00
abstract：:Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0609925
更新日期：2006-12-14 00:00:00
abstract：:Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good l...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a022
更新日期：1986-10-01 00:00:00
abstract：:The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl mod...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801609s
更新日期：2009-06-25 00:00:00
abstract：:Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00188a019
更新日期：1979-02-01 00:00:00
abstract：:In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0303711
更新日期：2004-02-26 00:00:00
abstract：:A series of substituted chromone-2-carboxylic acids was synthesized and tested as antagonists of SRS-A induced contractions of isolated guinea pig ileum. This work led to the discovery of sodium 7-[3-(4-acetyl-3hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (FPL 55712) which is...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a012
更新日期：1977-03-01 00:00:00
abstract：:The preparation and testing of the two racemic diastereoisomers and the four optically active enantiomers of the title compound in in vitro and in vivo models for determining potential antipsychotic activity are described. Both racemic diastereoisomers and two of the four chiral enantiomers are potent and long-acting ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00182a025
更新日期：1980-08-01 00:00:00
abstract：:A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compound 1a [(E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00123a012
更新日期：1989-03-01 00:00:00
abstract：:Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfenta...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00126a040
更新日期：1989-06-01 00:00:00
abstract：:In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01488
更新日期：2020-12-10 00:00:00
abstract：:The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051200u
更新日期：2006-02-23 00:00:00
abstract：:Analogues of nicotinic acid adenine dinucleotide phosphate (NAADP) with substitution at either the 4- or the 5-position position of the nicotinic acid moiety have been synthesized from NADP enzymatically using Aplysia californica ADP-ribosyl cyclase or mammalian NAD glycohydrolase. Substitution at the 4-position of th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1007209
更新日期：2010-11-11 00:00:00
abstract：:The N332 high-mannose glycan on the HIV-1 gp120 V3-loop is the target of many bNAbs. About 17% HIV isolates carry the N332 to N334 mutation, but the antibody recognition of the N334 N-glycan and its immunogenicity are not well characterized. Here we report the chemoenzymatic synthesis, antigenicity, and immunogenicity...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01290
更新日期：2018-11-21 00:00:00
abstract：:Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00164a024
更新日期：1990-02-01 00:00:00
abstract：:1-(Tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU), which is named Ftorafur or FT-207 and is used clinically as an antitumor agent, was conveniently synthesized by condensation of the trimethylsilyl derivative of 5-fluorouracil with 2-acetoxytetrahydrofuran using NaI as a catalyst. This optically inactive Thf-FU was res...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00222a011
更新日期：1977-12-01 00:00:00
